The mu opioid receptor mediates morphine-induced tumor necrosis factor and interleukin-6 inhibition in toll-like receptor 2-stimulated monocytes

Anesth Analg. 2008 Apr;106(4):1142-9, table of contents. doi: 10.1213/ane.0b013e318165de89.


Background: Morphine possesses immunomodulatory effects but its intrinsic mechanisms, especially in the toll-like receptor 2 (TLR2) signaling pathway, are only partially understood. In this study, we evaluated the effects of morphine on tumor necrosis factor (TNF), interleukin-6 (IL-6), and interleukin-10 (IL-10) production in TLR2-stimulated human monocytes and identified the involvement of the different opioid receptors, and of the lymphocyte-to-monocyte contact.

Methods: Peripheral blood mononuclear cells (PBMCs) were isolated from fresh blood by centrifugation on a density gradient. Monocytes were secondarily separated using a high-gradient magnetic cell sorting kit with specific anti-CD14 antibodies. Monocytes or PBMCs were pretreated with opioid receptors antagonists before being cultured with morphine and peptidoglycan (PGN) from Staphylococcus aureus (specific TLR2 agonist). The amount of TNF, IL-6, and IL-10 was measured in the supernatant enzyme-linked immunosorbent assay.

Results: Proinflammatory cytokines: Morphine significantly inhibited the production of cytokines in a dose and concentration-dependent manner in PGN-stimulated monocytes. Mu opioid receptor activation specifically mediated this morphine-induced TNF and IL-6 inhibition in monocytes. Morphine significantly inhibited the TNF, but not the IL-6 production, in PGN-stimulated PBMCs. The mu opioid receptor was not involved in this morphine-induced TNF inhibition in PBMCs. Antiinflammatory cytokines: IL-10 was not a factor for the inhibition of TNF and IL-6 production after PGN stimulation in either monocytes or PBMCs cultures.

Conclusions: The mu opioid receptor mediates morphine-induced TNF and IL-6 inhibition in PGN-stimulated monocytes, but not in PBMCs. A direct monocyte-to-lymphocyte contact (PBMCs) alters the inhibitory effects of morphine observed on monocytes alone. IL-10 is not a factor for the inhibition of TNF or for IL-6 production. Interactions between TLR2 and mu opioid intracellular pathways remain to be studied to delineate these morphine immunosuppressive effects.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Cell Separation / methods
  • Cells, Cultured
  • Cytokines / physiology
  • Humans
  • Inflammation
  • Interleukin-6 / adverse effects*
  • Monocytes / cytology
  • Monocytes / drug effects
  • Monocytes / physiology*
  • Morphine / pharmacology*
  • Naltrexone / analogs & derivatives
  • Naltrexone / pharmacology
  • Narcotic Antagonists / pharmacology
  • Receptors, Opioid, mu / antagonists & inhibitors
  • Receptors, Opioid, mu / drug effects
  • Receptors, Opioid, mu / physiology*
  • Toll-Like Receptor 2 / physiology*
  • Tumor Necrosis Factor-alpha / antagonists & inhibitors*


  • Cytokines
  • Interleukin-6
  • Narcotic Antagonists
  • Receptors, Opioid, mu
  • TLR2 protein, human
  • Toll-Like Receptor 2
  • Tumor Necrosis Factor-alpha
  • naltrindole benzofuran
  • Naltrexone
  • Morphine